Novel, potent and selective cyclin D1/CDK4 inhibitors: indolo[6,7-a]pyrrolo[3,4-c]carbazoles

Engler, Thomas A.; Furness, Kelly; Malhotra, Sushant; Sanchez-Martinez, Concha; Shih, Chuan; Xie, Walter; Zhu, Guoxin; Zhou, Xun; Conner, Scott E.; Faul, Margaret M.; Sullivan, Kevin A.; Kolis, Stanley P.; Brooks, Harold B.; Patel, Bharvin K.R.; Schultz, Richard M.; DeHahn, Tammy B.; Kirmani, Kashif; Spencer, Charles D.; Watkins, Scott A.; Considine, Eileen L.; Dempsey, Jack; Ogg, Catherine A.; Stamm, Nancy B.; Anderson, Bryan D.; Campbell, Robert M.; Vasudevan, Vasu; Lytle, Michelle L.

doi:10.1016/s0960-894x(03)00461-x

Cited by 56 publications

(19 citation statements)

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“…miR-503 has been demonstrated to downregulate cyclin D1 expression and induce G0/G1 phase cell cycle arrest in several cell types [5, 7, 14]. We confirmed that arcyriaflavin A induced cell cycle arrest in the G1 phase of ECSCs.…”

Section: Discussionsupporting

confidence: 80%

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Arcyriaflavin a, a cyclin D1–cyclin-dependent kinase4 inhibitor, induces apoptosis and inhibits proliferation of human endometriotic stromal cells: a potential therapeutic agent in endometriosis

Hirakawa

Nasu

Aoyagi

et al. 2017

Reprod Biol Endocrinol

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BackgroundWe previously showed that microRNA-503 (miR-503) transfection into endometriotic cyst stromal cells (ECSCs) induced cell cycle arrest at the G0/G1 phase by suppressing cyclin D1. This finding prompted us to evaluate the potential therapeutic effects of cyclin D1 inhibitors in endometriotic cells. This study aimed to determine whether arcyriaflavin A, a representative inhibitor of cyclin D1–cyclin-dependent kinase 4 (CDK4), is beneficial in the treatment of endometriosis.MethodsECSCs were isolated from the ovarian endometriotic tissues of 32 women. The effects of arcyriaflavin A on cell viability and proliferation, vascular endothelial growth factor A expression, apoptosis, and cell cycle progression were evaluated using a modified methylthiazoletetrazolium assay, enzyme-linked immunosorbent assay (ELISA), Caspase-Glo® 3/7 assay, and flow cytometry.ResultsArcyriaflavin A significantly inhibited cell viability, proliferation, and angiogenesis of ECSCs as assessed using the 5-bromo-2-deoxyuridine (BrdU) and methylthiazoletetrazolium bromide (MTT) assays, and vascular endothelial growth factor (VEGF) ELISA. Arcyriaflavin A induced apoptosis as shown in the Caspase-Glo® 3/7 assay and cell death detection ELISA whilethe cell cycle was arrested at the G0/G1 phase.ConclusionThe findings indicate that cyclin D1–CDK4 inhibitors may be promising candidates for the treatment of endometriosis. This is the first study to demonstrate the potential usefulness of arcyriaflavin A as a therapeutic agent for endometriosis. Further studies of the effects of cyclin D1–CDK4 inhibitors on endometriosis may provide useful information on pathogenesis and treatment.

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Section: Discussionsupporting

confidence: 80%

“…Cyclin D1 interacts with the enzymes CDK 4/6 to regulate cell cycle progression from the G1 phase to the S phase [7]. There are few reports on the effects of cyclin D1–CDK4 inhibitors on endometriosis.…”

Section: Introductionmentioning

confidence: 99%

Arcyriaflavin a, a cyclin D1–cyclin-dependent kinase4 inhibitor, induces apoptosis and inhibits proliferation of human endometriotic stromal cells: a potential therapeutic agent in endometriosis

Hirakawa

Nasu

Aoyagi

et al. 2017

Reprod Biol Endocrinol

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“…A variety of small molecule CDK2 inhibitors have been described, and some of these are currently in clinical trials [10]. More recently, specific CDK4 inhibitors have also been reported [11][12][13]. One of the challenges in developing molecular targeted anticancer agents is the identification of cell lines that are dependent on these targets for growth, and to determine their suitability as cellular models for evaluation of these agents.…”

Section: Introductionmentioning

confidence: 99%

Validation of cyclin D1/CDK4 as an anticancer drug target in MCF-7 breast cancer cells: Effect of regulated overexpression of cyclin D1 and siRNA-mediated inhibition of endogenous cyclin D1 and CDK4 expression

Grillo¹,

Bott²,

Khandke³

et al. 2005

Breast Cancer Res Treat

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We have examined the role of cyclin D1 and cyclin-dependent kinase-4 (CDK4) in the cell cycle progression and proliferation of MCF-7 breast cancer cells. Forced expression of cyclin D1 using a tetracycline-regulated expression system, and suppression of endogenous cyclin D1 and CDK4 using small interfering RNA (siRNA) were used to validate this protein complex as a drug target in cancer drug discovery. Overexpression of cyclin D1 increased both phosphorylation of the retinoblastoma gene product (RB) and passage through the G1-S phase transition, resulting in increased proliferation of cells. When cyclin D1 expression was shut off, growth rates fell below those seen in control cell lines transfected with the vector, indicating an increased dependence on this protein for proliferation. Inhibition of endogenous cyclin D1 or CDK4 expression by RNA interference resulted in hypophosphorylation of RB and accumulation of cells in G1. These results support the prevailing view that pharmacological inhibition of cyclin D1/CDK4 complexes is a useful strategy to inhibit the growth of tumors. Furthermore, since MCF-7 cells appear to be dependent on this pathway for their continued proliferation, it is a suitable cell line to test novel cyclin D1/CDK4 inhibitors.

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“…To test the inhibitory effects of the indocarbazoles against D1-CdK4, phosphorylation of Rb was measured 27 Selective inhibitors were identified by derivatization from indolocarbazoles, but without the sugar moiety found in UCN-01 or staurosporine. Both maleimide and carbonyl groups are important for enzyme interaction.…”

Section: Inhibitors Of Cyclin-dependent Kinases (Cdks)mentioning

confidence: 99%

Natural Products from Terrestrial Microbial Organisms with Cytotoxic Cell Cycle Inhibitors

Dreis¹,

Gartner²,

Krebs³

et al. 2014

Biodiversity, Natural Products and Cancer Treatment

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Many microbial products have the potential for therapeutic application, e.g. as anticancer drugs. This chapter presents natural products from terrestrial microbial organisms that attack various targets in tumor cells, e.g. cell cycle inhibitors (inhibitors of phosphoinositide-3-kinase, checkpoint kinase inhibitors, inhibitors of dual specificity phosphatases, inhibitors of cyclin-dependent kinases), inhibitors of histone deacetylases, topoisomerases, or growth factors as well as inhibitors of the proteasome, of heat shock protein 90, nuclear trafficking, or ATPase.New cancer drugs are most likely be used as part of combination therapy regimens. Attacking different targets in tumor cells may kill tumor cells resistant to one target. The potential of novel target-directed compounds to eradicate otherwise drug-resistant cells is an attractive perspective, which deserves further investigation.

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Novel, potent and selective cyclin D1/CDK4 inhibitors: indolo[6,7-a]pyrrolo[3,4-c]carbazoles

Cited by 56 publications

References 50 publications

Arcyriaflavin a, a cyclin D1–cyclin-dependent kinase4 inhibitor, induces apoptosis and inhibits proliferation of human endometriotic stromal cells: a potential therapeutic agent in endometriosis

Arcyriaflavin a, a cyclin D1–cyclin-dependent kinase4 inhibitor, induces apoptosis and inhibits proliferation of human endometriotic stromal cells: a potential therapeutic agent in endometriosis

Validation of cyclin D1/CDK4 as an anticancer drug target in MCF-7 breast cancer cells: Effect of regulated overexpression of cyclin D1 and siRNA-mediated inhibition of endogenous cyclin D1 and CDK4 expression

Natural Products from Terrestrial Microbial Organisms with Cytotoxic Cell Cycle Inhibitors

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